The present invention relates to a process for the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate.
Ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate is an important starting material for the preparation of antihypertensive drug viz. Doxazosin. It is usually prepared by the condensation of N-(2,3-dihydrobenzo[1,4]dioxin-2-carbonyl) piperazine with 4-amino-2-chloro-6,7-dimethoxyquinazoline[J. Med. Chem, 1987, 30(1), 49]. N-(2,3-dihydrobenzo[1,4]dioxin-2-carbonyl) piperazine is a condensation product of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate and piperazine.
Ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate was earlier prepared in 76% yield by condensation of catechol and 2,3-dibromopropionate in dry acetone in the presence of anhydrous potassium carbonate. The procedure requires the addition of potassium carbonate and dibromoester in four lots, over a period of 18 h. [J. Am. Chem. 80c. 1955, 77, 5374]. In the reported procedure, the formation of side product viz. ethyl-2-bromoacrylate (lachrymatic) is unavoidable and requires rigorous purification to isolate the desired product.
In view of the low yields and formation of side product (lachrymatic) in the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate, it is necessary to develop an alternative method in which higher yields of the desired product is obtained without the formation of lachrymatic side product.
The main objective of the present invention is to provide a process for the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate of the Formula-I see FIG. 1.
The another object of the present invention is to provide a process for the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate in hydrocarbon solvent in the presence of a base and catalytic amount of a phase transfer catalyst.
Accordingly, the present invention provides a process for the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate of the formula-1, which comprises reacting catechol with a base in a molar ratio of catechol to base in the range of 1:1 to 1:2 in a hydrocarbon solvent, removing the water by heating the reaction mixture at reflux temperature of the solvent, adding polyethylene glycol as phase transfer catalyst and 2,3-dibromopropionate to the above said reaction mixture and controlling the frothing by slowly adding alkali metal carbonate, stirring the resultant reaction mixture for a period of 3-10 hrs at a temperature ranging from 70-150xc2x0 C., filtering the reaction mixture and washing the filtrate followed by concentration to obtain the desired product.
In an embodiment of the present invention the base used is selected from potassium hydroxide and potassium carbonate.
In an another embodiment the hydrocarbon solvent used is toluene In yet another embodiment the alkali metal carbonate used is selected from sodium carbonate and potassium carbonate.
The process of the present invention is detailed below:
In the improved process for the preparation of ethyl 2,3-dihydrobenzo[1,4]dioxin-2-carboxylate, a solution of catechol in a hydrocarbon solvent was reacted with base at a temperature preferably in the range of 100-120xc2x0 C. for a period preferably in the range of 1-2 h using a Dean-Stark apparatus. To the above reaction mixture, polyethylene glycol and 2,3-dibromopropionate were added followed by slow addition of anhydrous potassium carbonate or sodium carbonate at the same temperature. It was refluxed for a period in the range of 2-6 h. The reaction mixture was filtered, filtrate washed with water, dried, and distilled to get the desired product.